Structural adaptation of the microcirculation is crucial for a wide variety of physiological events such as endurance training, adaptation to a cold environment, embryonic development, normal tissue repair, and reproductive function. The proposed studies represent a continuing effort to better understand the role of hypoxia/ischemia-inducible growth factors, especially vascular endothelial growth factor (VEGF) and its receptors (VEGF-R), but also basic fibroblast growth factor (bFGF) and transforming growth factor-beta1 (TGF-beta1), in the feedback regulation of blood vessel growth in a rt model of exercise conditioning. Our central hypothesis is the following: Exercise-induced hypoxia up-regulates VEGF, VEGF-R, and b-FGF; and, down-regulates TGF-beta1. When the vasculature has developed sufficiently, and tissue oxygenation is adequate even during periods of peak muscular activity, the expression of VEGF, VEGF-R, bFGF and TGF-beta return to nearly normal levels, stopping the further development of the vasculature. The propose work will utilize an integrative approach, employing mathematical analyses, experimentation in chronically instrumented rats in which skeletal muscles are stimulated electrically, and morphometry, stereology, immunohistochemistry, and biochemical techniques to address the following major questions: (Aim I) Is the expression of VEGF and its receptors subject to negative feedback control in chronically stimulated muscle? (Aim II) Is the expression of bFGF and TGF-beta1 modulated by a hypoxic environment, and are these growth factors subject to negative feedback control in electrically stimulated muscle? (Aim III) Can the dynamics of VEGF secretion, stimulation of angiogenesis, and/or storage of VEGF in the tissues account for a concept of growth regulation in which angiogenesis is driven by the maximum metabolic needs of a tissue, rather than the average needs? By understanding better the feedback regulation of VEGF, VEGF-R, bFGF, and TGF-beta1 in electrically stimulated muscle, can eventually integrate our findings with those from other laboratories to establish a comprehensive system analysis of blood vessel growth regulation.